SKP-SC-EVs-derived miRNA-30a-5p promote angiogenesis in peripheral nerve regeneration by targeting Lif and ANGPT2

Ischemia and hypoxia caused by vascular injury aggravate nerve injury. The extracellular vesicles from skin precursor-derived Schwann cells (SKP-SC-EVs) have proven to be beneficial to the regeneration of peripheral nerve injury, but whether SKP-SC-EVs can repair injured peripheral nerves by promoting angiogenesis remains unclear. Here, we found that SKP-SC-EVs enhanced the angiogenesis, which were verified by the transparency of tissue engineered nerve graft (TENG) and ultrasonic blood flow imaging. In vitro we verified that SKP-SC-EVs promote the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), which were traditionally used for the evaluating angiogenesis capacity. Furthermore, the expression pattern of microRNA (miRNA) in SKP-SC-EVs was profiled and functional experiments were screened. Notably, miR-30a-5p was selected because of the remarkably pro-angiogenic ability in vivo and in vitro, which was similar to the effects of SKP-SC-EVs. Luciferase reporter assay and functional experiments revealed miR-30a-5p contained in SKP-SC-EVs promoted angiogenesis by targeting ANGPT2 and LIF in the insufficient of VEGFa. Taken together, miR-30a-5p enriched in SKP-SC-EVs may be a key regulator of angiogenesis for the cell-free treatment for peripheral nerve injury. Examination of the expression pattern of microRNA in SKP-SC-EVs